5th time the charm for Tagrisso’s reimbursement extension?

Makes progress for reimb in the first line... eyes on whether results will be made within the year

Failed to pass CDDC deliberations several times due to OS data issues in Asian subpopulation, etc

Passes the first step to its reimbursement for the first time after 5 attempts...DREC and HIPDC deliberations processes remain to its reimbursement.

Will the process be completed within the year? AZ expresses its will to make its best efforts

After five attempts, the EGFR mutation-positive non-small cell lung cancer (NSCLC) treatment ‘Tagrisso (osimertinib)’ finally crossed the first hurdle to receiving reimbursement as a first-line treatment.

 

Although other procedures such as deliberation by the Health Insurance Review and Assessment Service’s Drug Reimbursement Evaluation Committee remain, the fact that it had overcome the highest barrier to reimbursement, the Cancer Disease Deliberation Committee review, 4 years after its indication was expanded to the first line, is regarded an achievement.

 

HIRA’s CDDC held its second 2023 Reimbursement Standard Deliberation Meeting for Anticancer Drugs on the 22nd and established reimbursement standards for Tagrisso.

 

The CDDC determined it was appropriate to set reimbursement standards for Tagrisso as a ‘first-line treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) mutations.’ With the decision, the drug was able to pass the first gateway for third-generation EGFR-targeted anti-cancer therapies to receive reimbursement as a first-line treatment.

 

◆Passes CDDC review after 5 attempts...sees fruition 4 years after indication expansion Tagrisso is a third-generation targeted anticancer therapy that targets the EGFR mutation.

 

It inhibits both the EGFR mutation and T790M mutation that are represented by L858R and Exon 19 deletions.

 

As the drug has a high blood-brain barrier (BBB) permeability than first and second-generation EGFR-targeted therapies, Tagrisso has shown a superior effect in patients with brain metastasis.

 

Tagrisso, which added its first-line indication in December 2018 in Korea, attempted to extend its reimbursement to the indication in 2019.

 

However, the drug was unable to receive reimbursement as a first-line treatment for over 4 years.

 

AstraZeneca had attempted reimbursement for Tagrisso at the CDDC level 4 times since 2019 and failed every attempt.

 

When Tagrisso’s reimbursement to the first line first emerged as an agenda in the second half of 2018, the government had been in favor of extending reimbursement.

 

However, the favorable stance faltered with the release of the Asian subgroup analysis results from a global Phase III trial in 2019.

 

The FLAURA trial assessed the efficacy and safety of Tagrisso in the first line, and the Asian subgroup analysis results of this global trial had risen as a barrier to its reimbursement as its hazard ratio (HR) was 0.995.

 

An HR of 0.995 indicates that the difference between Tagrisso and the control group is 0.005, which could be interpreted as the difference being insignificantly small.

 

After such results were disclosed, the CDDC in October 2019 decided to defer its decision until the full data from the Phase 3 FLAURA trial was released.

 

The company made its second attempt, submitting the overall OS data of FLAURA in 2020.

 

However, due to the rapid spread of COVID-19, the CDDC meeting that was set for February of the year had been pushed back and canceled several times and finally held at the end of April.

 

The reimbursement standards for the drug had not been set then either.

 

Although AstraZeneca expressed their will to accept most of the cost-sharing plan proposed by the government in consideration of the Asian subgroup data, the reimbursement fell through due to strong opposition from committee members that raised the issue of the drug’s clinical efficacy.

 

In September of the same year, the company made its third attempt powered by results from the FLAURA China study that confirmed improved OS in Asians.

 

The FLAURA China trial data analyzed a cohort of 136 Chinese patients that included 19 Chinese patients from the global FLAURA trial as well as 117 patients from a trial that had been separately conducted.

 

Results showed that the median PFS of the Tagrisso group was 17.8 months, which was comparable to the results from the global study.

 

Median OS in the Tagrisso group was 33.1 months, 7.4 months longer than the 25.7 months in the control group.

 

This is a higher OS improvement than the 6.8 months identified in the global trial.

 

The third reimbursement extension discussions for Tagrisso were made in April 2021.

 

The third attempt also resulted in failure.

 

At the time, CDDC members concluded that the OS value from the FLAURA China trial lacked statistical significance.

 

After the third attempt failed, patient groups rose to the occasion.

 

After Tagrisso's failure to receive reimbursement in April, 1,713 lung cancer patients and their families sent a joint statement to the government imploring the government to extend Tagrisso’s reimbursement to the first line as in many major countries.

 

Academic societies also criticized how only Tagrisso is not being reimbursed as first-line treatment in Korea.

 

3 months after its third setback, AstraZeneca applied for the 4th time to extend reimbursement.

 

This time, the company adopted a strategy of narrowing part of its reimbursement standards.

 

The company excluded Exon 21 mutation from the 'EGFR exon 19 deletion or exon 21 (L858R) mutation NSCLC’ it had been indicated for.

 

The company narrowed the criteria to 'first-line treatment for patients with EGFR exon 19 deletion and brain metastases' and reapplied for reimbursement.

 

The plan was to increase the clinical value of the drug by excluding the patient group that showed a relatively small difference in efficacy from the control group.

 

However, Tagrisso’s reimbursement extension was rejected at the CDDC meeting that was held in November 2021.

 

Real-world study on first-line Tagrisso use in Japan.

 

OS results according to gene mutation status (Data: ESMO)

This reluctant sentiment on Tagrisso’s reimbursement extension was reversed at the end of last year with the release of large-scale real-world data on Tagrisso’s use in the first line in Asia and Europe.

 

Analysis of real-world data on 660 Japanese patients confirmed a longer progression-free survival period (20.0 months) and an overall survival period of more than 3 years (40.9 months) than those identified in the Phase III trial.

 

With this data, the company put an end to Tagrisso’s efficacy controversy in Asia.

 

AstraZeneca took on its 5th challenge with this new data and a plan to lower drug prices as supplements.

 

The patient organizations’ petition requestion reimbursement extension also added support.

 

The 'Petition regarding the request for first-line treatment of the lung cancer treatment Tagrisso’ that was uploaded to the e-People website in February was sent to the National Assembly Health and Welfare Committee for deliberation after receiving over 50,000 consents.

 

As a result, after 5 attempts in the course of the past 4 years, Tagrisso finally made it through the first barrier to its reimbursement and passed the CDDC review.

 

◆Can it be reimbursed within the year?

 

Depends on DREC progress Although it has passed the high barrier of CDDC review, many procedures still remain for its reimbursement extension.

 

For anticancer drugs, CDDC review is only the first step of many.

 

The agenda has to pass HIRA’s Drug Reimbursement Evaluation Committee (DREC), and then undergo pricing negotiation with the NHIS, then pass MOHW’s Health Insurance Policy Deliberation Committee (HIPDC) review to complete all the procedures required to extend benefits.

 

Tagrisso is subject to the risk-sharing agreement (RSA) scheme and must pass the pharmacoeconomic evaluation.

 

HIRA’s statuary evaluation period is set to 120 days or less, but it is common for HIRA to exceed the set deadline if the company is required to submit supplementary data.

 

After completing discussions with HIRA and passing DREC review, the company has to conduct drug pricing negotiations with NHIS for up to 60 days.

 

Within 30 days from the period, MOHW’s HIPCD will deliberate and then issue a notification on the new drug price and then list the drug for extended reimbursement.

 

In other words, at maximum, Tagrisso’s reimbursement extension is set to be made by the end of this year.

 

The decisive step in advancing or delaying this timing of Tagrisso's reimbursement is expected to depend on DREC’s stage, where the pharmacoeconomic evaluation takes place.

 

If DREC requests supplementary data repeatedly, reimbursement listing may be delayed indefinitely.

 

In fact, several anticancer drugs have not been deliberated for over a year at the DREC level after passing the CDDC review.

 

In the case of MSD's Keytruda, which succeeded in extending reimbursement to the first-line treatment of NSCLC after 4 years, Keytruda’s reimbursement agenda was presented to DREC 6 months after passing the CDDC review in July 2021.

 

Although the company showed a high willingness to negotiate the reimbursement of Keytruda, the process was only completed eight months after passing the CDDC review due to a delay in its schedule, such as an unsuccessful submission for the DREC review in November 2021.

 

AstraZeneca plans to make the best efforts to extend Tagrisso's reimbursement within the year.

 

The company said, "We welcome the CDDC’s decision and would like to express our thanks to the government and committee members for making efforts to enable this.

 

We will continue to do our best to complete the procedures that remain and receive the reimbursement decision”